Insulin Modulation of Nitric Oxide in Diabetes and Islet Transplantation

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In rodent models of transplantation (Lewis rat and C57BL/6 mouse) and diabetes (BB/W rat and NOD mouse), islet dysfunction was hypothesized to be mediated by nitric oxide. I observed, in rats after islet transplantation, both increased systemic NO levels and iNOS gene expression. Peri-islet macrophages and islets were the source of NO production. Inhibition of post-transplant NO production improved early islet function and engraftment. Relatedly, streptozotocin-treated rodents and rodents predisposed to autoimmune-mediated diabetes had elevated systemic and macrophage culture levels of NO. I hypothesized that the elevated systemic levels of NO were due to the hypo- insulinemic state that is pathopneumonic of Type 1 diabetes. In support of this hypothesis, insulin administration in diabetic rodents reduced both systemic NO levels and macrophage NO/iNOS activity. I then hypothesized that TGF-β1 mediated insulin suppression of the NO/iNOS pathway. Importantly, concomitant with insulin's suppression of the macrophage NO/iNOS pathway was increased systemic and macrophage culture levels of TGF-β1. Furthermore, insulin administration in the rat minimal islet transplant model improved islet graft function, suppressed the NO/iNOS pathway, and increased systemic and macrophage culture levels of TGF-β1.

In summary, the data presented in this thesis demonstrates that: (1) NO mediates islet dysfunction in rodent models of transplantation and autoimmune diabetes; (2) insulin's salubrious properties in these models is mediated, at least in part, by the suppression of the macrophage NO/iNOS pathway by increased macrophage production of TGF-β1. Thus, insulin may act as an immunomodulatory hormone by suppression of the macrophages NO/iNOS pathway via control of TGF-β1 metabolism.

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